• Immune basis of Allergic Diseases, presented by Prof. dr. Ilija Jeftic from Integrated Academic Studies of Pharmacy.

Hypersensitivity Reactions

• Pathological immune reactions are considered excessive or inappropriate immune responses.
• Hypersensitivity reactions do not correspond to the causative agent or the type of cells and molecules involved in pathogenesis.
• It can either be an impaired qualitatively inadequate, or uncontrolled quantitatively altered immune response to foreign antigens, resulting in tissue damage.
• It can also be the immune response directed towards one's own antigens, which is autoimmunity.
• Early and late reactions are determined by the time required for the reaction to occur from contact with the antigen.
• Divided in 4 types according to the pathogenesis of immune damage, they are:
  • Type I: early hypersensitivity, anaphylactic type.
  • Type II: cytotoxic.
  • Type III: immunocomplex type.
  • Type IV: late type, T cell-mediated hypersensitivity.
• Type I hypersensitivity is characterized by the creation of allergen-specific IgE antibodies and their binding to the membrane of mast cells and basophilic leukocytes.
• Type II hypersensitivity is characterized by the binding of IgG and IgM class antibodies to antigens on the membrane of one's own cells.
• Type III hypersensitivity develops when the immune complexes are deposited, causing activation of the complement system and accumulation of neutrophil leukocytes.
• Type IV hypersensitivity is the only form, that is not mediated by antibodies, but by antigen-specific T cells.

Type I Hypersensitivity

• Allergic reactions of type I hypersensitivity are called anaphylactic reactions (anaphylaxis).
• Genetic and environmental factors both contribute to early hypersensitivity reactions.
• Familial tendency to the occurrence of type I hypersensitivity reactions is called atopy, and people predisposed to its development are called atopies.
• Atopic patients react atypically to common allergens by activating Th2 lymphocytes, which results in excessive production of IgE antibodies.

Etiology; Genetic Factors

• The potential role of gene products in disease is:
  • IL-4 and IL-13 stimulate the synthesis of IgE.
  • IL-5 stimulates the proliferation and activation of eosinophils.
  • CD14 interacts with TLR4, influencing the balance between Th1 and Th2 response to antigen.
  • The ẞ2-adrenergic receptor regulates the contraction of bronchial smooth muscles.
  • Some alleles regulate T cell response to allergens.
  • It participates in the activation of mast cells
  • Receptor subunit for both IL-4 and IL-13
  • A metalloproteinase involved in airway remodeling
  • Peptidases that can regulate the action of chemokines and cytokines

Etiology; Environmental Factors

• ALLERGENS are antigens that cause allergic reactions in genetically predisposed individuals.
• Characteristics of allergens:
  • Proteins and glycoproteins
  • Enzymatic activity
  • Very soluble
  • Stable
  • Low molecular weight
• Low concentrations in the environment
• Common Allergens include:
  • Proteins:
    • Foreign Serum.
    • Vaccines.
  • Foods:
    • Nuts.
    • Seafood.
    • Eggs.
    • Peas, beans, milk
  • Plant Pollens:
    • Rye grass.
    • Ragweed.
    • Timothy grass.
    • Birch trees.
• Drugs:
  • Penicillin.
  • Sulfonamides.
  • Local anesthetics.
  • Salicyclates.
• Insect Products:
  • Bee venom.
  • Wasp venom.
  • Ant venom.
  • Cockroach calyx.
  • Dust mites
  • Mold spores
• Animal hair and dander
• Latex
• The common allergens are:
• Pollen
• Mites
• Pet hair
• Drugs
• Insect Products
• Nutritional Allergens like peanuts, soy, fish, seafood, sesame etc.

Type 1 Hypersensitive Reactions - Pathogenesis

• During the first contact with an allergen, a specific clone of B lymphocytes is activated, beginning the synthesis of IgE class antibodies.
• IgE antibody production depends on T lymphocyte activation specific for allergen epitopes.
• Synthesized IgE antibodies:
  • Immediately bind to high-affinity receptors on the mast cell membrane (FcεRI).
  • Other remains binds to identical receptors on basophilic leukocytes.
• Upon re-exposure (another contact), the allergen binds to antibodies on the membrane of mast cells and basophilic leukocytes and occurs.
• Degranulation of previously formed mediators occurs from granules. Activation of enzymes that synthesize lipid mediators happens. Transcription, translation and secretion of cytokines also occurs.
• FcεRI receptor on the membrane of mast cells and basophils.
• Activation of mast cells with degranulation begins with the binding of allergens to IgE antibodies on the mast cell membrane.
• During the first contact with the allergen, IgE binds via its CH3 domain to high-affinity receptors on the mast cell membrane (FcεRI).
• A very small IgE amount is found in traces in the serum (0.0003 mg/ml)
• Upon re-contact, the allergen binds to cell-bound IgE, crosslinking it and triggering mast cell degranulation.
• Anaphylactoid reaction: direct stimulation of mast cell degranulation (iodine contrast agents, local anesthetics, dextran, lectins-phytohemagglutinin, concavalin A...).

Type I Hypersensitive Reactions - Pathogenesis Phases

• Early phase:
  • A consequence of mast cell activation and mediator production.
  • Vasodilatation, increased blood vessel permeability, and smooth muscle spasm occur.
• Late phase:
  • Begins 2-24 hours after contact with the allergen.
  • Characterized by the accumulation of inflammatory cells (eosinophilic leukocytes).
  • Occurrence of tissue damage.

Mediators; Type I Hypersensitivity

• The most important mediators are:
  • Histamine
    • causes dilation of small blood vessels
    • increases vascular permeability
    • stimulates transient contraction of smooth muscles.
  • Proteases - they damage the surrounding tissue.
• Arachidonic acid Metabolites
  • Prostaglandins that cause vasodilation.
  • Leukotrienes that stimulate prolonged contraction of smooth muscles.
• Cytokines
  • Induce a local inflammatory reaction.
  • Stimulate the mobilization of leukocytes (eosinophils, neutrophils and Th2 cells).
• Inflammatory amine, increases localized blood flow and blood vessel permeability and initiates smooth muscle contraction from Histamine.
  • Causes loss of blood pressure, constriction of airways, difficulty breathing, diarrhea, and vomiting.
  • Can be fatal in severe cases causing suffocation and anaphylactic shock.
• Mast-cell chymase, tryptase, and serine esterases activates matrix metalloproteinases which causes destruction to tissues.
• Tumor Necrosis Factor (TNF) Initiates influx of inflammatory leukocytes and lymphocytes into tissues and will cause Systemic inflammation
• Leukotrienes and platelet-activating factor (PAF) cause smooth muscle contraction, vascular permeability, mucus secretion, and activates leukocytes which contribute to the late-phase response that results in constricted airways, difficulty breathing, diarrhea, & or vomiting .
• Cytokines: IL-4 and IL-3 which Amplify Th2 Response and Increases production and activation of eosinophils, then Signals body to produce more IgE. which cause Inflammation, tissue damage, swelling, shortness of breath

Clinical Manifestation

• The cause of this type of reactions depends on:
  • The nature of the allergen.
  • Ways of allergen entry.
  • The number, localisation and characteristics of mast cells and other cells in the target organ.
  • The sensitivity of the target organ to the mediator effects.

Allergic Rhinitis

• Type I hypersensitivity clinical manifestation.
• Occurs seasonally (pollen) or throughout the year (house dust, dust mites).
• Allergic rhinitis is a consequence of the activation of mast cells in the nasal mucosa by allergens.
• Manifested by increased secretion, sneezing and obstruction of the nasal cavity after exposure to the allergen because the key mediators involved in this, are- histamine.

Allergic Conjunctivitis

• Also called seasonal conjunctivitis.
• Manifested by increased secretion, redness, irritation and itching.
• Causes recurring outbreaks of conjunctival inflammation and watery eyes from being a consequence of the activation of mast cells in the conjunctiva by allergens
• Occurs seasonally (pollen) or throughout the year (house dust, dust mites).

Bronchial Asthma

• A disease characterized by intermittent and reversible airway obstruction.
• Chronic bronchial inflammation by eosinophilic leukocytes, as well as a population of CD4+ NKT cells that recognize glycolipid antigens.
• Hyperactivity of bronchial smooth muscles to bronchoconstriction stimulation.
• Early phase is a consequence of the release of mediators.

Early Phase

• Histamine causes vasodilation.
• Prostaglandins lead to bronchoconstriction.
• Leukotrienes lead to increased production of mucus.

Late Phase

• Local infiltration by eosinophils, neutrophils and Th2 cells results in increased cytokine secretions.

Drugs Used In Treatment

• Bronchodilators
• Beta 2 Antagonists
• methylxanthines
• Anti-inflammatory Agents
• corticosteroids
• Lipoxygenase Inhibitors
• Receptor Blockers – antibodies

Anaphylaxis

• A systemic form of type I hypersensitivity that is a result of allergens in circulation.
• Typically occurs following injection.
• Insects.
• Absorption through internal organ epithelial surfaces .
• Anaphylactic reactions.
• Anaphylactoid reactions.

Anaphylactic

• it is an immune mediated reaction
• IgE antibody has an important role
• reactions causes direct release of histamine and other mediators from the mast.

Anaphylactoid

• is a non immune mediated reaction -No IgE involved
• does not cause degranulation
• The allergen [antigen] reacts with the IgE antibody and the Mast cell complex causes degranulation and release of histamine and Other Mediators.

Urticaria And Angioedema

• Urticaria- physical sign not a disease.
• There are transient episodes of circumscribed, edematous and erythematous Lesions with raised edges that are accompanied by pruritus - Occurs as a result of a sudden, local accumulation of fluid in the Skin.
• Angioedema- involved deeper in skin and mucous membranes
• Mechanism: complement activation , Ige etc

Atopic Dermatitis

• Type I hypersensitivity reaction localized in the skin ( is is acute or chronic)
• Acute reactions (acute eczema)
• Occur after local contact with an allergen on the skin's surface
• After a allergen binds to Ige antibodies on the mast Cell membrane, histamine will Be released causing vasodilation and increased Vascular permeability
• effects blocked by antihistamines
• It is a Biphasic inflammation with an initial TH2 phase while TH1 lymphocytes dominate with chronic lesions
• the diagnostic of atopic dermatitis is based on a clinic picture and on the basis OF personal and family history with strong genetic predisposition Important enviromental Factors- House mite as a provocative; Food Intolernace ; Staph

Type II Hypersensitivity (Cytotoxic)

• Lymphocytes are activated by antigens that are expressed on the cell membrane with activated B lymphocytes and synthesize antibodies that bind to membrane receptors and the Effector begins (activation of complement system) -Phagocytosis ADCCreaction = antibofy , the process where a target cell coated with antibodies is destroyed

Type III Hypersensitivity (Immune Complex-mediated)

• Diseases caused by immune complexes arise as a result of excessive protection of immune and they cannot be removed by the circulation as they are deposited in the tissues.
  • complexes primarily found in - small Arteries, glomeroli and joint synovium, the pathological and clinical manifestations of these diseases are vasculitis, and nephritis arthritis. -This types are systemic The antigen -atibody complexes -excert their pathogenic effect after disposition tissues

Type IV. Hypersensitivity Cell Mediated

• Mediated by T- Lymphocytes.
• Occurs as consequence of.Autoimmune process or excess persistent Response to Environmental Antitens
• Autoimmune reaction Directed against cellular ANTIGENS
• LIMITED Tissue Distribution types: Contact ; tuberculin; granulomatous
• Involves in various T-cell-mediated disease with tissue damage caused by inflammation
• Involved the cytokines, that activate memory T-cells upon the next allergen exposure.
• Contact dermitities- hapten passes thru epidermis and body forns complexes which activate T cells =During next contact there is infiltration and domage

Explore the nuances of hypersensitivity, differentiating antibody-mediated and non-antibody-mediated reactions. Understand the genetic predispositions and immune responses leading to conditions like atopy. Discover how cytokine and receptor activities influence these reactions.